image: The biological motor protein kinesin was discovered at the Marine Biological Laboratory in Woods Hole, Mass., through studies of the giant axon of the longfin inshore squid (Doryteuthis pealeii, formerly in Loligo). view more
Credit: Tom Kleindinst
WOODS HOLE, MASS.—Scientists who invented new ways to study how "cargo" is moved within cells and, as a result, discovered a new biological motor protein, kinesin, at the Marine Biological Laboratory (MBL) in Woods Hole, Mass., have received the prestigious 2012 Lasker Award for Basic Medical Research, the Albert and Mary Lasker Foundation announced today. The awardees are Michael Sheetz of Columbia University; James Spudich of Stanford University School of Medicine; and Ron Vale of University of California, San Francisco/Howard Hughes Medical Institute.
The Lasker Awards are among the most respected science prizes in the world, and often anticipate future recipients of the Nobel Prize. Also announced today were the recipients of the 2012 Lasker Award for Clinical Research (Roy Calne and Thomas E. Starzl) and for Special Achievement (Donald D. Brown and Thomas Maniatis). The awards carry a $250,000 honorarium for each category.
"The Lasker Awards celebrate biomedical research that has had a transformative effect on the practice of medicine, science, and the lives and health of people all over the world," says Alfred Sommer, chair of the Lasker Foundation's Board of Directors. "This year's awards are no exception, honoring fundamental biological discoveries, life-saving surgical techniques and scientific statesmanship of the highest order."
Sheetz, Spudich, and Vale opened up the study of "cytoskeletal motor proteins, machines that move cargoes within cells, contract muscles, and enable cell movements.…. The miniscule motors underlie numerous vital processes, and the landmark achievements of Vale, Spudich, and Sheetz are driving drug-discovery efforts aimed at cardiac problems as well as cancer," states the Lasker Foundation announcement.
The Lasker Foundation has provided a detailed description of the trio's discoveries. To hear Vale describe them, see this iBioSeminars video: http://www.ibiomagazine.org/issues/august-issue/molecular-motor-search.html.
A Classic MBL Collaboration
The motor protein discoveries recognized by the Lasker Award coalesced during an intense period of scientific investigation at the MBL (1983 to 1985) involving several labs. Key elements at the MBL were essential to the discoveries, including an abundance of squid, the organism in which the investigations were conducted; the landmark introduction of video-enhanced microscopy at the MBL, independently made by Robert Allen of Dartmouth College and Shinya Inoué of MBL; and an environment dedicated to risk-taking science and collaborations among researchers from all over the world.
"It was fully in the spirit of MBL, in the sense of collaborations without boundaries. The MBL gave us the opportunity to just get down and do the science," says Sheetz.
Vale first became involved in this research as a graduate student at Stanford University in 1982. At the time, Vale was interested in how material is transported inside nerve cells (neurons), which in humans can be more than three feet long. For example, Vale says, "a motor neuron that starts in your spinal cord, where its nucleus and DNA reside, extends a long, thin tube called an axon all the way to your foot, where it can stimulate a muscle to contract. Inside the axon, building blocks such as proteins that are made in your spinal cord have to be continually shipped to your foot, to keep the nerve cell alive and functional. And very little was known about this transport process in the 1980s."
Vale had been inspired by two landmark 1982 papers by Robert Allen, Scott Brady, and Ray Lasek in which they used Allen's video-enhanced microscopy to make movies of axonal transport in the squid. The squid has what Vale calls "the granddaddy of all axons," being over 100 times larger in diameter than a human axon. Video-enhanced microscopy dramatically increased the contrast of the images, allowing one to see details that could never be seen before. "What they saw was absolutely fantastic," Vale says. "All these little dots [organelles] zipping along the axon, moving between the cell body and the nerve terminal. It was really thrilling to watch."
Meanwhile, in a lab downstairs at Stanford, Spudich and Sheetz (who was on sabbatical from University of Connecticut) were successfully developing a way to study the motion of myosin—a motor protein known to cause muscle movement—in a test tube. Vale was intrigued by their research, and began to wonder if axonal transport might be explained by a similar myosin mechanism. He and Sheetz decided to test out the idea in the squid giant axon.
But 1983 was a year of El Niño, and not a squid was to be found in the warm waters off California. So Sheetz and Vale came to the MBL, where there was plenty of squid from the cold Atlantic. Originally they collaborated with Allen's and Lasek's labs, but by the end of the summer they had teamed up instead with Tom Reese and Bruce Schnapp of the National Institutes of Health, who had a year-round lab the MBL. All of these labs were working intently on axonal transport, and all made important contributions to the final picture. (For a detailed scientific discussion, see Salmon, ED, Trends Cell Biol. 1995 Apr; 5(4):154-8.)
Through what Vale calls a "tour de force" experiment, Schnapp and Reese showed that axonal transport in the squid took place on tracks called microtubules. This meant the motor protein couldn't be myosin, which is associated with other tracks, called actin. The culminating observation, the one that enabled the purification of kinesin, came at 2 AM one summer night in 1984 when Vale and Sheetz looked at the video screen and saw "something totally shocking and surprising," Vale says. It was purified microtubules that Vale had isolated "bound to the glass surface [of the microscope slide] and crawling along like little snakes" in response to some mystery motor protein from the squid giant axon. To their surprise, the unknown motor was not just bound to the surface of the organelles it helps to move, as they had expected, but was a soluble motor protein that was activated by binding to glass. It was now just matter of tracking that motor protein down. Vale was so excited that he postponed his planned entry into medical school that fall to remain at MBL, where he and Sheetz continued studying the system all winter. Within a few months, they had purified the protein responsible for the movement, which they called kinesin (from the Greek root "kine" for motion.) Their work was published in a series of five papers in 1985.
The assays that Spudich, Vale and Sheetz developed to study myosin and kinesin "provided powerful tools that investigators worldwide began using to probe the process of intracellular and muscular movement," notes the Lasker Foundation announcement. "Today we know that humans have dozens of myosins and kinesins. The proteins differ in their mechanistic details, but they share characteristics that provoke movement. The miniscule motors underlie numerous vital processes and hold promise as therapeutic targets…Through their vision, ingenuity, and persistence, Sheetz, Spudich and Vale opened the study of molecular motors and illuminated crucial features of a fundamental biological process."
The MBL's unique role as a crossroads where the nation's best scientists come together and collaborate was vital to this work. "It would be very hard to imagine doing this without an institution like the MBL," says Reese, who has come to the MBL for nearly 40 years to conduct research and teach in the Neurobiology course. "It was a perfect team, as we all brought different skills and thinking and enjoyed the camaraderie of working on the problem," says Vale, also a current MBL investigator and former co-director of the Physiology course. "Great ideas proliferate at the MBL," he says.
The Marine Biological Laboratory (MBL) is dedicated to scientific discovery and improving the human condition through research and education in biology, biomedicine, and environmental science. Founded in 1888 in Woods Hole, Massachusetts, the MBL is an independent, nonprofit corporation.